Insomnia with objective but not subjective short sleep duration is associated with incident cardiovascular and/or cerebrovascular disease.

STUDY OBJECTIVES: Insomnia with objective short sleep duration (ISSD) has been associated with cardiometabolic outcomes (ie, hypertension or diabetes). We examined whether ISSD, based on objective or subjective sleep measures, is associated with more serious health problems, such as incident cardiovascular and/or cerebrovascular disease (CBVD). METHODS: 1,258 men and women from the Penn State Adult Cohort (56.9% women, aged 48.3 ± 12.95 years) without CBVD at baseline were followed up for 9.21 ± 4.08 years. The presence of CBVD was defined as a history of diagnosis or treatment of heart disease and/or stroke. Insomnia was defined as a complaint of insomnia with a duration ≥ 1 year. Poor sleep was defined as a complaint of difficulty falling asleep, staying asleep, nonrestorative sleep, or early morning awakening. Objective short sleep duration was defined as < 6 hours' sleep based on polysomnography. Subjective short sleep duration was based on the median self-reported percentage of sleep time (ie, < 7 hours). RESULTS: Compared with normal sleepers with normal sleep duration, the highest risk of incident CBVD was in the ISSD group (odds ratio = 2.46, 95% confidence interval = 1.04-5.79), and the second highest was in normal sleepers with short sleep duration (odds ratio = 1.68, 95% confidence interval = 1.11-2.54). The risk of incident CBVD was not significantly increased in poor sleepers or those with insomnia with normal sleep duration. Finally, insomnia with subjective short sleep duration was not associated with increased incident CBVD. CONCLUSIONS: These data add to the cumulative evidence that ISSD, based on objective but not subjective measures, is the more severe biological phenotype of the disorder associated with incident CBVD. CITATION: Pejovic S, Vgontzas AN, Fernandez-Mendoza J, et al. Insomnia with objective but not subjective short sleep duration is associated with incident cardiovascular and/or cerebrovascular disease. J Clin Sleep Med. 2024;20(7):1049-1057.

Age-related differences in the association of mild-to-moderate sleep apnea with incident cardiovascular and cerebrovascular diseases.

BACKGROUND: Mild-to-moderate obstructive sleep apnea (mmOSA) is highly prevalent in the general population. However, studies on its association with incident cardiovascular and/or cerebrovascular disease (CBVD) are limited. We examined the association between mild-to-moderate OSA and incident cardiovascular and/or cerebrovascular (CBVD) in a general population sample, and whether age modifies this association. METHODS: A total of 1173 adults from the Penn State Adult Cohort (20-88 years) without CBVD or severe OSA at baseline were followed-up after 9.2 (±4.1) years. Incident CBVD was defined based on a self-report of a physician diagnosis or treatment for heart disease and/or stroke. Logistic regression examined the association of mild-to-moderate OSA (AHI 5-29.9) with incident CBVD and the combined effect of mmOSA and MetS on incident CBVD after adjusting for multiple confounders. RESULTS: Age significantly modified the association between mmOSA with incident CBVD (p-interaction = 0.04). Mild-to-moderate OSA was significantly associated with incident CBVD in adults aged <60 years (OR = 1.74, 95%CI = 1.06-2.88, p = 0.029), but not in adults aged ≥60 years (OR = 0.71, 95%CI = 0.39-1.27, p = 0.247). Even mild OSA (AHI 5-14.9) carried a significant risk for incident CBDV in adults aged <60 years (OR = 1.86, 95%CI = 1.05-3.28, p = 0.032). An additive effect was found between mmOSA and MetS with incident CBVD in those aged <65 years (OR = 3.84, 95%CI = 1.95-7.56, p<0.001). CONCLUSIONS: The risk of incident CBVD is increased in young and middle-aged but not older adults with mmOSA, which may affect the way we currently diagnose and treat this highly prevalent sleep-related breathing disorder.

Sex differences in macular thickness of the retina in patients with psychosis spectrum disorders.

INTRODUCTION: Imaging of retinal structure in psychosis spectrum disorders (PSD) is a novel approach to studying effect of this illness class on CNS structure. Studies of optical coherence tomography (OCT) have revealed significant reductions in regarding: retinal nerve fiber layer (RNFL), macular thickness (MT), ganglion cell-inner plexiform layer (GC-IPL) and macular volume (MV). Sex differences in retinal structure in PSD have not been previously explored. METHODS: This cross-sectional pilot study included 81 participant of age matched patients and controls. There were no differences between genders regarding illness duration and antipsychotic daily dose in the patient group. SD-OCT assessed RNFL, GC-IPL, MT, MV, and optic nerve cup-to-disc (C/D) ratio. In order to assess the main effects of illness, sex, and illness × sex interaction on the retinal parameters, general linear model was performed. RESULTS: Patients demonstrated abnormalities on all OCT indices. Effects of sex were observed for central subfield MT and C/D ratio, which were lower in females. An illness × sex interaction effect was observed for the left MT, indicating greater thinning in female patients. CONCLUSION: Sex differences in OCT findings in PSD appear to be most prominent considering macular parameters. These preliminary data may have important implications for the valid interpretation of OCT findings as potential biomarkers for PSD.

Retinal structural abnormalities in young adults with psychosis spectrum disorders.

BACKGROUND: Structural retinal architecture in living organisms became measurable with the development of optical coherence tomography (OCT) scanners. Single-layer analysis with spectral-domain OCT, among other techniques, may provide further insight into pathological changes in complex brain disorders such as psychosis spectrum disorders (PSD). METHODS: This study investigated potential thinning of retinal layers (retinal nerve fiber layer - RNFL, macular volume, macular thickness, ganglion cell-inner plexiform layer- GC-IPL, optic cup volume and cup-to-disk ratio) using a spectral-domain OCT device in 33 non-acute PSD patients (illness duration 5.9 ± 3.9 years) and 35 healthy controls. RESULTS: In comparison to age and gender matched controls, patients had bilateral reductions in GC-IPL layer thickness and macular volume. Macular central subfield thinning was found in the right eye, while average macular thickness was lower in the left eye only. RNFL thinning was not observed in patients in comparison to controls, but we noticed that status of this layer could be affected by daily dose of antipsychotics and by illness duration. CONCLUSION: Taken together, our results reveal that retinal thinning is present in young adults with PSDs, but in comparison to the literature we found more prominent changes in both GC-IPL and macular volume/thickness, than in RNFL. Our findings may reflect synaptic loss and neuronal atrophy in non-acute young patients with psychosis.

Psychomotor Vigilance Test and Its Association With Daytime Sleepiness and Inflammation in Sleep Apnea: Clinical Implications.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a key symptom of obstructive sleep apnea (OSA). The Psychomotor Vigilance Task (PVT) has been suggested as an objective easy-to-use, inexpensive alternative to the Multiple Sleep Latency Test (MSLT) to measure EDS. In patients with OSA, physiological sleepiness, but not subjective EDS (Epworth Sleepiness Scale [ESS]), has been associated with increased levels of the sleep- inducing proinflammatory cytokine interleukin-6 (IL-6). The goal of this study was to assess the association of PVT with objectively measured sleepiness (MSLT) and subjectively measured sleepiness (ESS) and IL-6 levels in patients with OSA. METHODS: We studied 58 untreated patients with OSA who underwent an 8-hour in-laboratory polysomnography for 4 consecutive nights. MSLT, PVT, and 24-hour serial profiles of IL-6 were assessed on the fourth day. PVT variables included number of lapses, mean reciprocal of the fastest 10% and slowest 10% reaction times, and median of 1/reaction time. ESS was assessed on day 1 of the study. RESULTS: Higher ESS scores were significantly associated with greater number of lapses (ß = .34, P = .02) and lower values of 1/RT (ß = -.36, P = .01) and slowest 10% RTs (ß = -.30, P = .04). No significant association was observed between PVT and MSLT, nor PVT and IL-6 levels. CONCLUSIONS: Our findings suggest that PVT is associated with subjectively assessed daytime sleepiness, but not with physiological sleepiness nor IL-6 levels in patients with OSA. It appears that ESS and PVT may be useful in predicting risks associated with impaired performance, such as traffic accidents, in patients with OSA.

Objective, but Not Subjective, Sleepiness is Associated With Inflammation in Sleep Apnea.

Study objectives: Objective and subjective measures of excessive daytime sleepiness (EDS) are only weakly associated. No study, however, has examined whether these two measures of EDS differ in terms of underlying mechanisms and prognostic value. Pro-inflammatory cytokines, that is, interleukin-6 (IL-6) appear to promote sleepiness/fatigue, while the stress hormone cortisol promotes vigilance. We hypothesized that objective sleepiness is associated with increased levels of IL-6 and decreased levels of cortisol. Methods: We studied 58 obstructive sleep apnea (OSA) patients with clinical EDS and/or cardiovascular comorbidities who underwent 8-hour in-lab polysomnography for four consecutive nights. Objective and subjective daytime sleepiness were measured by Multiple Sleep Latency Test (MSLT), Epworth Sleepiness Scale (ESS), and Stanford Sleepiness Scale (SSS), respectively. Twenty-four-hour profiles of IL-6 and cortisol levels were assessed on the fourth day. Results: The agreement between objective and subjective EDS in OSA patients was fair (kappa = 0.22). Objective EDS (lower MSLT) in OSA patients was associated with significantly elevated 24-hour (ß = -0.34, p = .01), daytime (ß = -0.30, p = .02) and nighttime (ß = -0.38, p < .01) IL-6 levels, and significantly decreased daytime (ß = 0.35, p = .01) cortisol levels. In contrast, subjective EDS (higher ESS/SSS) was not associated with either elevated IL-6 levels or decreased cortisol levels. Conclusions: Our findings suggest that OSA with objective EDS is the more severe phenotype of the disorder associated with low-grade inflammation, a link to cardiometabolic morbidity and mortality. Compared to subjective EDS, objective EDS is a stronger predictor of OSA severity and may be useful in the clinical management of the disorder.

Sleep apnoea and the hypothalamic-pituitary-adrenal axis in men and women: effects of continuous positive airway pressure.

Previous findings on the association of obstructive sleep apnoea (OSA) and the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, partly due to the confounding effect of obesity and infrequent sampling. Our goal was to examine whether in a relatively nonobese population, OSA is associated with elevated cortisol levels and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (sham-CPAP) use.72 subjects (35 middle-aged males and post-menopausal females with OSA, and 37 male and female controls) were studied in the sleep laboratory for four nights. 24-h blood sampling was performed every hour on the fourth day and night in the sleep laboratory at baseline, after sham-CPAP and after CPAP treatment.In both apnoeic men and women, OSA was associated with significantly higher 24-h cortisol levels compared with controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.These results suggest that OSA in nonobese men and slightly obese women is associated with HPA axis activation, similar albeit stronger compared with obese individuals with sleep apnoea. Short-term CPAP use decreased cortisol levels significantly compared with baseline, indicating that CPAP may have a protective effect against comorbidities frequently associated with chronic activation of the HPA axis, e.g. hypertension.

Short- and Long-Term Sleep Stability in Insomniacs and Healthy Controls.

STUDY OBJECTIVES: Assess the short- and long-term stability of sleep duration in patients with insomnia and normal-sleeping controls. DESIGN: Observational short-term and prospective studies. SETTING: Sleep laboratory. PARTICIPANTS: Patients with insomnia (n = 150) and controls (n = 151) were recruited from the local community or sleep disorders clinic. A subsample of 95 men from the Penn State Adult Cohort (PSAC) were followed up 2.6 y after their initial visit. MEASUREMENTS: Participants underwent a physical examination and 8-h polysomnography (PSG) recording for 3 consecutive nights (controls and insomniacs), or 2 single nights separated by several years (PSAC). Intraclass correlation coefficients (ICCs) assessed the stability of the variables total sleep time (TST), sleep onset latency (SOL), and wake after sleep onset (WASO). We also examined persistence of the first-night classification of "short" versus "normal" sleep duration on subsequent nights. RESULTS: Stability of TST, SOL, and WASO based on 1 night were slight to moderate in both patients with insomnia (ICC = 0.37-0.57) and controls (ICC = 0.39-0.59), and became substantial to almost perfect when based on the average of 3 nights (ICC = 0.64-0.81). We observed similar degrees of stability for TST and WASO in the longitudinal sample, with moderate stability based on a single night and substantial stability based on both nights. In examining the persistence of "short" and "normal" sleep duration, 71.4% (controls), 74.7% (patients with insomnia), and 72.6% (longitudinal sample) of participants retained their first-night classifications over subsequent nights. CONCLUSIONS: Sleep duration variables, particularly total sleep time based on 3 consecutive nights in both patients with insomnia and controls or two single-night recordings separated by several years, are stable and reflect a person's habitual sleep. Furthermore, a single night in the laboratory may be useful for reliably classifying one's sleep duration.

Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the 'unitary' hypothesis.

BACKGROUND: Since chronic fatigue syndrome (CFS) and fibromyalgia (FM) often co-exist, some believe they reflect the same process, somatization. Against that hypothesis are data suggesting FM but not CFS was common in patients with sleep-disordered breathing (SDB). The presence of discrete case definitions for CFS and FM allowed us to explore rates of CFS alone, CFS with FM, and FM alone in SDB patients compared to those with sleep complaints that fulfilled criteria for insomnia. METHODS: Participants were 175 sequential patients with sleep-related symptoms (122 had SDB and 21 had insomnia) and 39 healthy controls. Diagnoses were made by questionnaires, tender point count, and rule out labs; sleepiness was assessed with Epworth Sleepiness Scale and mood with Beck Depression Inventory. RESULTS: Rates of CFS, FM or CFS + FM were high: 13% in SDB and 48% in insomnia. CFS occurred frequently in SDB and insomnia, but FM occurred frequently only in insomnia. SDB patients with CFS and/or FM had higher daytime sleepiness than those without these disorders. CONCLUSION: CFS patients should complete Epworth scales, and sleep evaluation should be considered for those with scores ≥ 16 before receiving the diagnosis of CFS; the coexistence of depressed mood in these patients suggests some may be helped by treatment of their depression. That FM was underrepresented in SDB suggests FM and CFS may have different underlying pathophysiological causes.

Sleep apnoea, sleepiness, inflammation and insulin resistance in middle-aged males and females.

In obese males obstructive sleep apnoea (OSA) is associated with inflammation and insulin resistance; however, findings are confounded by adipose tissue, a hormone- and cytokine-secreting organ. Our goal was to examine whether in a relatively nonobese population, OSA is associated with sleepiness and inflammation/insulin resistance, and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (CPAP) use. 77 subjects, 38 middle-aged males and post-menopausal females with OSA and 39 male and female controls, were studied in the sleep laboratory for 4 nights. Measures of sleepiness (objective and subjective), performance, serial 24-h blood samples for interleukin (IL)-6, tumour necrosis factor receptor (TNFR)-1, leptin and adiponectin, and single samples for high-sensitivity C-reactive protein (hsCRP), fasting glucose and insulin levels were obtained. Apnoeic males were significantly sleepier and had significantly higher hsCRP, IL-6, leptin and insulin resistance than controls. Apnoeic females had significantly higher hsCRP; however, objective sleepiness, IL-6, TNFR-1, insulin resistance (Homeostatic Model Assessment index), leptin and adiponectin were similar to controls. CPAP improved subjective sleepiness, but no changes were observed in any of the biomarkers. In conclusion, OSA is associated with sleepiness, inflammation and insulin resistance, even in nonobese males, and this association is stronger in males than in females. Short-term CPAP does not improve the inflammatory/metabolic aberrations in OSA.

Effects of recovery sleep after one work week of mild sleep restriction on interleukin-6 and cortisol secretion and daytime sleepiness and performance.

One workweek of mild sleep restriction adversely impacts sleepiness, performance, and proinflammatory cytokines. Many individuals try to overcome these adverse effects by extending their sleep on weekends. To assess whether extended recovery sleep reverses the effects of mild sleep restriction on sleepiness/alertness, inflammation, and stress hormones, 30 healthy young men and women (mean age ± SD, 24.7 ± 3.5 yr; mean body mass index ± SD, 23.6 ± 2.4 kg/m(2)) participated in a sleep laboratory experiment of 13 nights [4 baseline nights (8 h/night), followed by 6 sleep restriction nights (6 h/night) and 3 recovery nights (10 h/night)]. Twenty-four-hour profiles of circulating IL-6 and cortisol, objective and subjective daytime sleepiness (Multiple Sleep Latency Test and Stanford Sleepiness Scale), and performance (Psychomotor Vigilance Task) were assessed on days 4 (baseline), 10 (after 1 wk of sleep restriction), and 13 (after 2 nights of recovery sleep). Serial 24-h IL-6 plasma levels increased significantly during sleep restriction and returned to baseline after recovery sleep. Serial 24-h cortisol levels during restriction did not change compared with baseline, but after recovery they were significantly lower. Subjective and objective sleepiness increased significantly after restriction and returned to baseline after recovery. In contrast, performance deteriorated significantly after restriction and did not improve after recovery. Extended recovery sleep over the weekend reverses the impact of one work week of mild sleep restriction on daytime sleepiness, fatigue, and IL-6 levels, reduces cortisol levels, but does not correct performance deficits. The long-term effects of a repeated sleep restriction/sleep recovery weekly cycle in humans remain unknown.

Insomnia with short sleep duration and mortality: the Penn State cohort.

STUDY OBJECTIVES: Because insomnia with objective short sleep duration is associated with increased morbidity, we examined the effects of this insomnia subtype on all-cause mortality. DESIGN: Longitudinal. SETTING: Sleep laboratory. PARTICIPANTS: 1,741 men and women randomly selected from Central Pennsylvania. MEASUREMENTS: Participants were studied in the sleep laboratory and were followed-up for 14 years (men) and 10 years (women). "Insomnia" was defined by a complaint of insomnia with duration > or = 1 year. "Normal sleeping" was defined as absence of insomnia. Polysomnographic sleep duration was classified into two categories: the "normal sleep duration group" subjects who slept > or = 6 h and the "short sleep duration group" subjects who slept < 6 h. We adjusted for age, race, education, body mass index, smoking, alcohol, depression, sleep disordered breathing, and sampling weight. RESULTS: The mortality rate was 21% for men and 5% for women. In men, mortality risk was significantly increased in insomniacs who slept less than 6 hours compared to the "normal sleep duration, no insomnia" group, (OR = 4.00, CI 1.14-13.99) after adjusting for diabetes, hypertension, and other confounders. Furthermore, there was a marginally significant trend (P = 0.15) towards higher mortality risk from insomnia and short sleep in patients with diabetes or hypertension (OR = 7.17, 95% CI 1.41-36.62) than in those without these comorbid conditions (OR = 1.45, 95% CI 0.13-16.14). In women, mortality was not associated with insomnia and short sleep duration. CONCLUSIONS: Insomnia with objective short sleep duration in men is associated with increased mortality, a risk that has been underestimated.

Leptin and hunger levels in young healthy adults after one night of sleep loss.

Short-term sleep curtailment associated with activation of the stress system in healthy, young adults has been shown to be associated with decreased leptin levels, impaired insulin sensitivity, and increased hunger and appetite. To assess the effects of one night of sleep loss in a less stressful environment on hunger, leptin, adiponectin, cortisol and blood pressure/heart rate, and whether a 2-h mid-afternoon nap reverses the changes associated with sleep loss, 21 young healthy individuals (10 men, 11 women) participated in a 7-day sleep deprivation experiment (four consecutive nights followed by one night of sleep loss and two recovery nights). Half of the subjects were randomly assigned to take a mid-afternoon nap (14:00-16:00 hours) the day following the night of total sleep loss. Serial 24-h blood sampling and hunger scales were completed on the fourth (predeprivation) and sixth day (postdeprivation). Leptin levels were significantly increased after one night of total sleep loss, whereas adiponectin, cortisol levels, blood pressure/heart rate, and hunger were not affected. Daytime napping did not influence the effects of sleep loss on leptin, adiponectin, or hunger. Acute sleep loss, in a less stressful environment, influences leptin levels in an opposite manner from that of short-term sleep curtailment associated with activation of the stress system. It appears that sleep loss associated with activation of the stress system but not sleep loss per se may lead to increased hunger and appetite and hormonal changes, which ultimately may lead to increased consumption of 'comfort' food and obesity.

Insomnia with objective short sleep duration is associated with deficits in neuropsychological performance: a general population study.

STUDY OBJECTIVES: To examine the joint effect of insomnia and objective short sleep duration on neuropsychological performance. DESIGN: Representative cross-sectional study. SETTING: Sleep laboratory. PARTICIPANTS: 1,741 men and women randomly selected from central Pennsylvania. INTERVENTIONS: None. MEASUREMENTS: Insomnia (n = 116) was defined by a complaint of insomnia with a duration > or = 1 year and the absence of sleep disordered breathing (SDB), while normal sleep (n = 562) was defined as the absence of insomnia, excessive daytime sleepiness, and SDB. Both groups were split according to polysomnographic sleep duration into 2 categories: > or = 6 h of sleep ("normal sleep duration") and < 6 h of sleep ("short sleep duration"). We compared the groups' performance on a comprehensive neuropsychological battery that measured processing speed, attention, visual memory, and verbal fluency, while controlling for age, race, gender, education, body mass index, and physical and mental health. RESULTS: No significant differences were detected between insomniacs and controls. However, the insomnia with short sleep duration group compared to the control with normal or short sleep duration groups showed poorer neuropsychological performance in variables such as processing speed, set-switching attention, and number of visual memory errors and omissions. In contrast, the insomnia with normal sleep duration group showed no significant deficits. CONCLUSIONS: Insomnia with objective short sleep duration is associated with deficits in set-switching attentional abilities, a key component of the "executive control of attention." These findings suggest that objective sleep duration may predict the severity of chronic insomnia, including its effect on neurocognitive function.

Insomnia with objective short sleep duration is associated with type 2 diabetes: A population-based study.

OBJECTIVE: We examined the joint effects of insomnia and objective short sleep duration, the combination of which is associated with higher morbidity, on diabetes risk. RESEARCH DESIGN AND METHODS: A total of 1,741 men and women randomly selected from Central Pennsylvania were studied in the sleep laboratory. Insomnia was defined by a complaint of insomnia with duration of >or=1 year, whereas poor sleep was defined as a complaint of difficulty falling asleep, staying asleep, or early final awakening. Polysomnographic sleep duration was classified into three categories: >or=6 h of sleep (top 50% of the sample); 5-6 h (approximately third quartile of the sample); and 126 mg/dl or use of medication. In the logistic regression model, we simultaneously adjusted for age, race, sex, BMI, smoking, alcohol use, depression, sleep-disordered breathing, and periodic limb movement. RESULTS: Chronic insomnia but not poor sleep was associated with a higher risk for diabetes. Compared with the normal sleeping and >or=6 h sleep duration group, the highest risk of diabetes was in individuals with insomnia and

Women sleep objectively better than men and the sleep of young women is more resilient to external stressors: effects of age and menopause.

The aims of this study were to: (i) assess gender differences of objective sleep patterns in a general population sample; (ii) evaluate the effects of menopause and hormone treatment (HT) on the sleep of the same cohort; and (iii) examine gender differences in sleep resilience towards external stressors. The participants were (i) 1324 subjects without sleep complaints, recruited from the general population of Central Pennsylvania that spent one night in the sleep laboratory and (ii) 66 young, healthy volunteers whose sleep was disturbed during night four by an external stressor, i.e. 24-h blood drawing (average of nights 2 and 3 versus night 4). Women compared with men in the general population sample had significantly higher percentage of sleep time, lower percentage of stage 1, and higher percentage of slow wave sleep. Also, menopause, in the absence of HT, was associated with prolonged sleep latency and decreased deep sleep. Finally, young, healthy women compared with men experienced less sleep disturbance because of blood draws as indicated by a significantly smaller change in per cent sleep time, and percentage of stage 1 sleep. These findings suggest that women without sleep complaints sleep objectively better across age than men and the sleep of young women is more resistant to external stressors. Also, gonadal hormones exert a beneficial effect on women's sleep. This gender dimorphism in sleep regulation may have been to protect women from the demands of infant and child care, and in part, might contribute to women's lower cardiovascular risks and greater longevity.

Obesity and sleep disturbances: meaningful sub-typing of obesity.

Obesity, excessive daytime sleepiness (EDS), and self-reported short sleep duration appear to be on the rise, while there is evidence that obesity and these sleep disorders are strongly connected. In this paper, we review data that challenge the common belief that the sleep apnoea and sleep loss, frequently associated with obesity, are the primary determinants of obesity-related objective daytime sleepiness and subjective fatigue (tiredness without increased sleep propensity). Specifically, obesity is associated with objective and subjective EDS regardless of the presence of sleep apnoea. The association between obesity and EDS was confirmed in recent studies of large random samples of the general population or clinical samples, which showed that the primary determinants of subjective EDS were depression, metabolic disturbances, i.e. obesity/diabetes and insulin resistance, and lack of physical activity, and, secondarily, sleep apnoea or sleep loss. Paradoxically, within the obese, with or without sleep apnoea, those who slept objectively better at night are sleepier (objectively) during the day than those who slept worse. The distinguishing factor between those that slept better vs. those that slept worse appears to be level of emotional stress. Furthermore, many studies reported that obesity is associated with self-reported short sleep duration; however, it appears that short sleep duration is a marker of emotional stress rather than a reflection of true sleep loss. Based on these data, we propose that obesity-related deeper sleep and objective EDS are primarily related to metabolic disturbances, whereas obesity-related poorer sleep and subjective fatigue appear to be the result of psychological distress. Furthermore, based on data from studies in normal controls and patients with sleep disorders, it appears that the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and pro-inflammatory cytokines determines the level of sleep/arousal within the 24-hour cycle, i.e. "eucortisolemia" or "hypocortisolemia" plus hypercytokinemia is associated with high sleep efficiency and objective sleepiness, whereas "hypercortisolemia" plus hypercytokinemia is associated with low sleep efficiency and fatigue. In conclusion, we propose that the above-reviewed data provide the basis for a meaningful phenotypic and pathophysiologic sub-typing of obesity. One subtype is associated with emotional distress, poor sleep, fatigue, HPA axis "hyperactivity," and hypercytokinemia while the other is associated with non-distress, better sleep but more sleepiness, HPA axis "normo or hypoactivity," and hypercytokinemia. This proposed sub-typing may lead to novel, preventive and therapeutic strategies for obesity and its associated sleep disturbances.

Lack of regular exercise, depression, and degree of apnea are predictors of excessive daytime sleepiness in patients with sleep apnea: sex differences.

BACKGROUND: Apnea, depression, and metabolic abnormalities are independent predictors of excessive daytime sleepiness (EDS) in patients with sleep apnea. Exercise is beneficial for apnea, depression, and metabolic abnormalities; however, its association with EDS is not known. STUDY OBJECTIVES: To evaluate the contribution of lack of regular exercise, depression, and apnea severity on daytime sleepiness in patients with sleep apnea. PARTICIPANTS AND DESIGN: One thousand one hundred six consecutive patients (741 men and 365 women) referred to the sleep disorders clinic for symptoms consistent with sleep apnea. Daytime sleepiness was assessed with the Epworth Sleepiness Scale and activity was evaluated with a quantifiable Physical Activity Questionnaire. RESULTS: Compared with women, men had a higher apnea hypopnea index (AHI) (40.4 +/- 1.2 vs 31.0 +/- 1.8), lower body mass index (BMI) (35.3 +/- 0.3 kg/m2 vs 39.6 +/- 0.5 kg/m2), and higher rate of regular exercise (39.1% vs 28.8%) ( p < 0.05). Linear regression analysis of the total sample after adjusting for age, BMI, sex, central nervous system medication, and diabetes showed that logAHI, depression, and lack of regular exercise were significant predictors of sleepiness. Predictors of mild or moderate sleepiness for both sexes were depression and logAHI, whereas predictors of severe sleepiness for men were lack of regular exercise, depression, and minimum SaO2 and, for women, logAHI. CONCLUSIONS: In obese apneic patients, lack of regular exercise (only in men), depression, and degree of apnea are significant predictors of EDS. This association is modified by sex and degree of sleepiness. Assessment and management of depression and physical exercise should be part of a thorough evaluation of patients with sleep apnea.

Plasma interleukin 6 levels are elevated in polycystic ovary syndrome independently of obesity or sleep apnea.

Premenopausal women with polycystic ovary syndrome (PCOS) are at a much higher risk for excessive daytime sleepiness, fatigue, and insulin resistance than control women. Elevated levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) are presumably part of the pathogenesis of these clinical manifestations. Forty-two obese women with PCOS, 17 body mass index-comparable obese controls, and 15 normal-weight controls free from apnea participated in the study that included one 8-hour nighttime polysomnography, single morning cytokine plasma concentrations, and insulin resistance indices. Women with PCOS exhibited higher plasma concentrations of IL-6 than obese controls, who had intermediate values, or normal-weight controls, who had the lowest values (4.75 +/- 0.5 vs 3.65 +/- 0.4 vs 1.84 +/- 0.3 pg/mL, P < .01). Tumor necrosis factor alpha values were higher in PCOS and obese controls compared with normal-weight controls, but the difference was not statistically significant (4.05 +/- 0.3 vs 3.79 +/- 0.2 vs 3.14 +/- 0.2 pg/mL, P = .103). Based on backward regression analysis, IL-6 levels had a stronger association with the PCOS group than with the obese group, and the sleep or hypoxia variables did not make a significant contribution to either IL-6 or TNF-alpha. Both IL-6 and TNF-alpha correlated positively with body mass index (P < .01) in obese controls but not in women with PCOS. Furthermore, within the PCOS group, IL-6 and TNF-alpha correlated more strongly with indices of insulin resistance than obesity. We conclude that IL-6 levels are elevated in obese women with PCOS independently of obesity or sleep apnea and may represent a pathophysiologic link to insulin resistance.